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Glucagon-like Peptide 2

https://doi.org/10.1016/S1043-2760(98)00136-2Get rights and content

Abstract

Glucagon-like peptide 2 (GLP-2) is secreted in a nutrient-dependent manner from enteroendocrine cells throughout the gastrointestinal tract and is trophic to the intestinal epithelial mucosa. GLP-2 acts via stimulation of crypt cell proliferation and inhibition of cell death. GLP-2 also stimulates intestinal glucose transport, decreases mucosal permeability, and shows therapeutic efficacy in experimental models of short bowel syndrome and both small and large bowel inflammation.

Section snippets

GLP-2 Synthesis, Secretion and Physiology

GLP-2, a 33 amino acid (aa) peptide, is highly conserved across different mammalian species. Like GLP-1, GLP-2 is secreted from enteroendocrine cells in a nutrient-dependent manner in both rodents and humans10, 11. Both GLP-1 and GLP-2 contain an alanine residue at position 2, rendering them ideal substrates for cleavage and inactivation by the enzyme dipeptidyl peptidase 4 (DPP-IV). Indeed, both GLP-2 (aa 1–33) and GLP-2 (aa 3–33) are detected in plasma from fasting rats and humans, and the

GLP-2 Action in Experimental Models of Intestinal Atrophy and Injury

A combination of biliary secretions, nutrients and growth factors is known to be important for maintenance and growth of the intestinal mucosal epithelium22. After fasting or parenteral feeding, intestinal weight drops rapidly in both the small and large bowel, primarily as a result of mucosal atrophy. Remarkably, co-infusion of GLP-2 and total parenteral nutrition (TPN) in fasted rats prevented mucosal atrophy and restored intestinal weight in the small, but not the large bowel23. These

Mechanism of GLP-2 Action

Most data on GLP-2 action derive from studies administering pharmacological amounts of GLP-2 or GLP-2 analogs to rodents. Although in- creased endogenous GLP-2 is associated with intestinal mucosal hyperplasia, GLP-2 antagonists are not yet widely available, and studies reporting immunoneutralization of GLP-2 action have not been reported. Furthermore, no animal models or human reports of GLP-2 deficiency have been reported, hence the central physiological significance of GLP-2 action for

GLP-2: Unanswered Questions

Although our understanding of GLP-2 action has advanced rapidly over the past several years, many important physiological questions remain unanswered. The relative physiological importance of GLP-2 for intestinal growth, adaptation to intestinal injury and maintenance of intestinal barrier function await studies using GLP-2 antagonists, immunoneutralizing GLP-2 antisera or GLP-2R knockout mice. Whether GLP-2 has an important role in the stomach or esophagus awaits further study. The precise

Acknowledgements

Work from the Drucker laboratory was supported by grants from the Medical Research Council of Canada and Allelix Biopharmaceuticals Inc. DJD is a Scientist of the Medical Research Council of Canada and a consultant to Allelix Biopharmaceuticals Inc.

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